Glucose is the primary energy source used by mammalian cells to sustain themselves and to accomplish their basic functions. Glucose can be introduced into the blood stream from dietary absorption, the breakdown of the glycogen (a glucose storage molecule) or the endogenous production of glucose from other raw materials (gluconeogenesis). The uptake of glucose into and out of the blood, through which it can be circulated throughout the body, is a critical homeostatic system, regulated by a diverse range of metabolic pathways. Healthy adult blood glucose typically ranges between 70-99 mg/dL, with the potential to spike as high as 140 mg/dL following a meal (Triplett, C. L. et al. (2012), Am J Manag Care 18, S4-S10). Blood sugar levels that fall above (hyperglycemia) or below (hypoglycemia) the typical ranges can lead to a variety of debilitating acute or chronic symptoms including but not limited to loss-of-consciousness, impaired vision, weight gain/loss, changes in consumptive behavior (hunger and thirst), neuropathy, cardiovascular dysfunction and even death. There are a number of diseases, pathological conditions and medications that can result in transient or persistent blood sugar dysregulation (Triplett, 2012). The blood glucose dysregulation disorder, diabetes melitus, is actually a cluster of metabolic diseases (including type I, type II, gestational diabetes and prediabetes) characterized by hyperglycemia. On the other hand, the primary treatment for diabetic hyperglycemia, insulin administration, can trigger an overreaction leading to potentially severe and life-threatening hypoglycemia, limiting the treatment options for some people (Cryer et al., (2003), Diabetes Care 26(6), 1902-1912). Thus there is a need for improved methods and agents to treat dysregulated blood glucose disorders such as hyperglycemia, hypoglycemia and diabetes.
The most critical and well-studied factor for regulating blood glucose (i.e., blood sugar) is the hormone insulin. Insulin reduces blood sugar by facilitating glucose transport into target cells, encouraging its conversion into glycogen and lipid storage, and by indirectly inhibiting gluconeogenesis in the liver (Triplett, 2012). Insulin is secreted by β-cells, which are a component of the pancreatic mini-organs, the islets of Langerhans (i.e. islets). A fundamental contributing cause of diabetes is diminished insulin secretion caused by a progressive loss of β-cell function and mass (Groop L., (2000). Int J Clin Pract Suppl 113, 3-13). β-cells are activated by a cascade of reactions, starting with the passage of glucose molecules through a transporter into the cell where its subsequent metabolism leads to a depolarization of the cell (i.e., an increase in positively charged ions). This depolarization activates voltage-dependent calcium (Ca+) channels that open to let in a flood of Ca+. The incoming Ca+ wave triggers exocytosis of the insulin-containing secretory vesicles out into the extracellular space. When blood glucose rises, more β-cell metabolites are produced, which then exaggerate the depolarization/Ca+ influx and increase the total insulin secretion back into the blood stream (Doyle, M. E. et al., (2003). Pharmacological Reviews 55(1), 105-131).
D-serine is an endogenous amino acid, derived from dietary consumption and from the racemization of L-serine through the enzyme serine racemase (Konno, R., et al., (2010), Chem Biodivers 7, 1450-1458; Miyoshi, Y., et al., (2011), J Chromatogr B Analyt Technol Biomed Life Sci 879, 3184-3189; Wolosker, H., et al., (1999), Proc Natl Acad Sci USA 96, 721-725). Although traditionally studied as a central nervous system (CNS) neurotransmitter, D-serine has been localized to the pancreas in both mice (˜11 pmol/mg tissue; Horio, M., et al., (2011), Neurochem Int 59, 853-859) and rats (˜15 nmol/g tissue; Imai, K., et al., (1998), Amino Acids 15, 351-361; Miyoshi, 2011). Intravenous injection of C14-labelled D-serine predominantly concentrated in the pancreas after 30 minutes, compared to the other peripheral organs examined in the rat (Imai et al., 1998). In the brain, extracellular D-serine uptake is primarily mediated by two transporter proteins (Shao, Z., et al., (2009), J Neurosci Res 87, 2520-2530) asc-1, which has also been observed in mouse (Fukasawa, Y., et al., (2000), J Biol Chem 275, 9690-9698) and human (Nakauchi, J., et al., (2000), Neurosci Lett 287, 231-235) pancreas and ASCT2, which is expressed in rat islets (Fukushima, D., et al., (2010), J Physiol Pharmacol 61, 265-271). The glycine transporter, GlyT1, which is critical for the maintenance of D-serine regulated synapses in the CNS, has also been found in the embryonic mouse pancreas (Jursky, F., and Nelson, N., (1996), J of Neurochem 67, 446-44). Furthermore, D-amino acid oxidase (DAO), D-serine's primary catabolic enzyme, appears to be active in the pancreas such that the DAO mutant rat demonstrates a 10-fold increase in pancreatic D-serine (Miyoshi, 2011). Despite these findings, the functional role of D-serine in the pancreas has not been examined.
D-serine's dominant function in the CNS is as a co-agonist of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) (Mothet, J-P., et al., (2000), PNAS 97, 4926-4931). These ionotropic glutamate receptors are activated by a convergence of coincident events including local depolarization, binding of the primary glutamate ligand, and requisite binding of a co-agonist typically resulting in a large depolarization of the post-synaptic cell through an influx of Na+ and Ca+ ions. The NMDAR is a heterotetrameric structure with two prerequisite GLUN1 co-agonist binding subunits and, most commonly, two glutamate-binding GLUN2 subunits, types A-D. While predominantly distributed in the CNS, functional NMDARs have also been located in peripheral organs, including the pancreas. GLUN2C cDNA was detected in human pancreatic tissue (Lin, Y. J., et al., (1996), Mol Brain Res 43, 57-64) and several subunit proteins (GLUN1, GLUN2C and GLUN2D) have been observed in multispecies β-cell lines (Gonoi, T., et al., (1994), J Biol Chem 269, 16989-16992; Molnar, E., et al., (1995), FEBS Lett 371, 253-257) and isolated rat islets (Molnar, 1995).
Currently there is a need for agents and/or methods that are useful for treating dysregulated blood glucose disorders. There is also a need for agents and/or methods that are useful for modulating blood glucose levels.